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Analysis of the in vitro and in vivo effects of photodynamic therapy on prostate cancer by using Protoporphyrin IX-polyamine derivatives
Abstracts / Photodiagnosis and Photodynamic Therapy 17 (2017) A4–A78
plexity of modelling and planning. While several other research groups engage in sophisticated treatment planning [1–3], their solutions remain complex, often proprietary, indication-specific, and reliant on expert operators. Our vision is the development of a shared, open-source, multi-indication research infrastructure for PDT treatment modelling, with the goal of accelerating discovery and lowering barriers to clinical translation by offering the community a platform to build on. To that end, we present here an image-to-plan workflow for PDT fluence field modelling, based on our fast and open-source FullMonte [4] tetrahedral Monte Carlo simulator, using open-source meshing [5] and visualization [6] libraries. Starting with a medical image, we delineate organs, generate a mesh, assign optical properties, place light sources, then simulate and visualize the resulting fluence field together with the solid model and medical images to predict clinical outcome. Presentation options include volume maps for solid organs, surface maps for hollow organs (e.g. bladder), and the familiar dose-volume histogram. We also have interactive 3D tools for placement of probes, both free-form and using planar templates. In previous work, we demonstrated fast MC run times in animal models [7]. We now present preliminary results from imagingderived human cases for multiple indications including bladder and breast. We use our fast simulator to explore the plan’s sensitivity to major sources of uncertainty including variability in optical properties and probe placement error, thus providing an indication of plan robustness.
References [1] [2] [3] [4] [5]
J. Swartling, et al., J. Biomed. Opt. (2010). S. Davidson, et al., Phys. Med. Biol. 54 (8) (2009). M. Huggett, et al., Proc. SPIE BiOS (2013) 85680J–85686J. J. Cassidy, V. Betz, L. Lilge, Proc. SPIE BiOS (2013) 85920H–86014H. The Computational Geometry Algorithms Library (CGAL), INRIA/Geometry Factory www.cgal.org. [6] The Visualization Toolkit (VTK), Kitware Inc. www.vtk.org. [7] J. Cassidy, V. Betz, L. Lilge, Front. Phys. 3 (6) (2015).
http://dx.doi.org/10.1016/j.pdpdt.2017.01.172 Poster PU-085 Analysis of the in vitro and in vivo effects of photodynamic therapy on prostate cancer by using Protoporphyrin IX-polyamine derivatives C. Fidanzi-Dugas 1,∗ , B. Liagre 1 , G. Chemin 1 , A. Perraud 2 , C. Carrion 3 , R. Granet 1 , V. Sol 1 , D.Y. Léger 1 1 Université de Limoges, Laboratoire de Chimie des Substances Naturelles, EA 1069 Limoges, France 2 Université de Limoges, Homéostasie Cellulaire et Pathologie, EA 3842 Limoges, France 3 Université de Limoges, CIM, UMR CNRS 7276, Limoges, France
Photodynamic therapy (PDT), using porphyrins as photosensitizers (PS), has been approved for the treatment of several solid tumors. We developed a new vectorization strategy based upon the chemical derivatization of Protoporphyrin IX (PpIX) with the two polyamines (PA), spermidine (PpIX-dSd) and spermine (PpIXdSm). PA, as well as their porphyrin derivatives (PpIX-PA), are actively transported and accumulated into cancer cells by the Polyamine Transport System (PTS). Phototoxicities of PpIX-PA have been assessed after red light irradiation of two Chinese hamster ovarian cell lines, CHO and CHO-MG (which differ from each other by their PTS activity), along with the human healthy prostate cell
A77
line RWPE-1 and three human prostate cancer cell lines, PC-3, DU 145 and LNCaP. We showed PA derivatization increased PS efficiency. Photoactivation of PpIX-PA triggered the intrinsic apoptotic pathway and also activated the COX-2/PGE2 pathway, known as an inducer of apoptosis resistance (through the p38/MAPK protein which is pro-apoptotic but also a positive regulator of COX-2). However, inhibition of COX-2 did not increase PDT efficiency and inhibition of p38/MAPK resulted in increased PDT-induced apoptosis. These PS also induced a reduction in expression of NF-B, a pro-survival factor. In vivo phototoxicities of PpIX-dSd and PpIX-dSm have been tested on PC-3 subcutaneous xenografts performed in nude mice. Tumor irradiation by red light of PpIX-dSd treated mice resulted in growth slowing and histological studies showed a drop in both the proliferative marker Ki67, and the anti-apoptotic protein Bcl-2 levels. Nevertheless, in vitro PpIX-dSm efficiency failed to be confirmed in vivo. So, PA-derivatization increased PpIX in vitro phototoxicity. Activation of the COX-2/PGE2 pathway did not seem to reduce PDT efficiency. Only PpIX-dSd, was found somewhat active on a murine model. Nevertheless, these data showed that these new PS could be good candidates in the context of prostate cancer treatment by PDT. http://dx.doi.org/10.1016/j.pdpdt.2017.01.173 Poster PU-086 Usage of reprication-eficient viral particle for photodynamic therapy against prostate cancer allows high cytotoxicity through different pathways N. Honda 1,∗ , M. Inai 2 , T. Furuyama 3 , Y.S. Hong 3 , H. Hazama 3 , H. Nakamura 4 , H. Yasuda 5 , T. Nishikawa 6 , Y. Kaneda 6 , K. Awazu 2,3,7 1 Institute for Academic Initiatives, Osaka University, Osaka, Japan 2 Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan 3 Graduate School of Engineering, Osaka University, Osaka, Japan 4 Institute of Innovative Research, Tokyo Institute of Technology, Kanagawa, Japan 5 Research Center for Ultra-High Voltage Electron Microscopy, Osaka University, Osaka, Japan 6 Graduate School of Medicine, Osaka University, Osaka, Japan 7 Global Center for Medical Engineering and Informatics, Osaka University, Osaka, Japan
Background: Occurrence rate of prostate cancer increases in men over 65, and with the world’s ageing society, incident rate of this disease will likely to increase in next decade. To tackle this problem, this study aims to establish effective photodynamic therapy (PDT) method against prostate malignancies. Replication-deficient viral vector, called hemagglutinating virus of Japan envelope (HVJ-E), was utilized to accomplish fast and effective drug deliverying system and lipidated protoporphyrin IX (PpIX lipid) was inserted via centrifugation, creating a novel photosensitizer named porphyrus envelope [1]. We herein report how porphyrus envelope allows rapid drug delivery via membrane fusion and exhibits high therapeutic efficacy. Methods: In vitro drug release mechanism of porphyrus envelope was analysed using transmission electron microscope (TEM). Next, localization of porphyrus envelope-PpIX lipid was analysed
plexity of modelling and planning. While several other research groups engage in sophisticated treatment planning [1–3], their solutions remain complex, often proprietary, indication-specific, and reliant on expert operators. Our vision is the development of a shared, open-source, multi-indication research infrastructure for PDT treatment modelling, with the goal of accelerating discovery and lowering barriers to clinical translation by offering the community a platform to build on. To that end, we present here an image-to-plan workflow for PDT fluence field modelling, based on our fast and open-source FullMonte [4] tetrahedral Monte Carlo simulator, using open-source meshing [5] and visualization [6] libraries. Starting with a medical image, we delineate organs, generate a mesh, assign optical properties, place light sources, then simulate and visualize the resulting fluence field together with the solid model and medical images to predict clinical outcome. Presentation options include volume maps for solid organs, surface maps for hollow organs (e.g. bladder), and the familiar dose-volume histogram. We also have interactive 3D tools for placement of probes, both free-form and using planar templates. In previous work, we demonstrated fast MC run times in animal models [7]. We now present preliminary results from imagingderived human cases for multiple indications including bladder and breast. We use our fast simulator to explore the plan’s sensitivity to major sources of uncertainty including variability in optical properties and probe placement error, thus providing an indication of plan robustness.
References [1] [2] [3] [4] [5]
J. Swartling, et al., J. Biomed. Opt. (2010). S. Davidson, et al., Phys. Med. Biol. 54 (8) (2009). M. Huggett, et al., Proc. SPIE BiOS (2013) 85680J–85686J. J. Cassidy, V. Betz, L. Lilge, Proc. SPIE BiOS (2013) 85920H–86014H. The Computational Geometry Algorithms Library (CGAL), INRIA/Geometry Factory www.cgal.org. [6] The Visualization Toolkit (VTK), Kitware Inc. www.vtk.org. [7] J. Cassidy, V. Betz, L. Lilge, Front. Phys. 3 (6) (2015).
http://dx.doi.org/10.1016/j.pdpdt.2017.01.172 Poster PU-085 Analysis of the in vitro and in vivo effects of photodynamic therapy on prostate cancer by using Protoporphyrin IX-polyamine derivatives C. Fidanzi-Dugas 1,∗ , B. Liagre 1 , G. Chemin 1 , A. Perraud 2 , C. Carrion 3 , R. Granet 1 , V. Sol 1 , D.Y. Léger 1 1 Université de Limoges, Laboratoire de Chimie des Substances Naturelles, EA 1069 Limoges, France 2 Université de Limoges, Homéostasie Cellulaire et Pathologie, EA 3842 Limoges, France 3 Université de Limoges, CIM, UMR CNRS 7276, Limoges, France
Photodynamic therapy (PDT), using porphyrins as photosensitizers (PS), has been approved for the treatment of several solid tumors. We developed a new vectorization strategy based upon the chemical derivatization of Protoporphyrin IX (PpIX) with the two polyamines (PA), spermidine (PpIX-dSd) and spermine (PpIXdSm). PA, as well as their porphyrin derivatives (PpIX-PA), are actively transported and accumulated into cancer cells by the Polyamine Transport System (PTS). Phototoxicities of PpIX-PA have been assessed after red light irradiation of two Chinese hamster ovarian cell lines, CHO and CHO-MG (which differ from each other by their PTS activity), along with the human healthy prostate cell
A77
line RWPE-1 and three human prostate cancer cell lines, PC-3, DU 145 and LNCaP. We showed PA derivatization increased PS efficiency. Photoactivation of PpIX-PA triggered the intrinsic apoptotic pathway and also activated the COX-2/PGE2 pathway, known as an inducer of apoptosis resistance (through the p38/MAPK protein which is pro-apoptotic but also a positive regulator of COX-2). However, inhibition of COX-2 did not increase PDT efficiency and inhibition of p38/MAPK resulted in increased PDT-induced apoptosis. These PS also induced a reduction in expression of NF-B, a pro-survival factor. In vivo phototoxicities of PpIX-dSd and PpIX-dSm have been tested on PC-3 subcutaneous xenografts performed in nude mice. Tumor irradiation by red light of PpIX-dSd treated mice resulted in growth slowing and histological studies showed a drop in both the proliferative marker Ki67, and the anti-apoptotic protein Bcl-2 levels. Nevertheless, in vitro PpIX-dSm efficiency failed to be confirmed in vivo. So, PA-derivatization increased PpIX in vitro phototoxicity. Activation of the COX-2/PGE2 pathway did not seem to reduce PDT efficiency. Only PpIX-dSd, was found somewhat active on a murine model. Nevertheless, these data showed that these new PS could be good candidates in the context of prostate cancer treatment by PDT. http://dx.doi.org/10.1016/j.pdpdt.2017.01.173 Poster PU-086 Usage of reprication-eficient viral particle for photodynamic therapy against prostate cancer allows high cytotoxicity through different pathways N. Honda 1,∗ , M. Inai 2 , T. Furuyama 3 , Y.S. Hong 3 , H. Hazama 3 , H. Nakamura 4 , H. Yasuda 5 , T. Nishikawa 6 , Y. Kaneda 6 , K. Awazu 2,3,7 1 Institute for Academic Initiatives, Osaka University, Osaka, Japan 2 Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan 3 Graduate School of Engineering, Osaka University, Osaka, Japan 4 Institute of Innovative Research, Tokyo Institute of Technology, Kanagawa, Japan 5 Research Center for Ultra-High Voltage Electron Microscopy, Osaka University, Osaka, Japan 6 Graduate School of Medicine, Osaka University, Osaka, Japan 7 Global Center for Medical Engineering and Informatics, Osaka University, Osaka, Japan
Background: Occurrence rate of prostate cancer increases in men over 65, and with the world’s ageing society, incident rate of this disease will likely to increase in next decade. To tackle this problem, this study aims to establish effective photodynamic therapy (PDT) method against prostate malignancies. Replication-deficient viral vector, called hemagglutinating virus of Japan envelope (HVJ-E), was utilized to accomplish fast and effective drug deliverying system and lipidated protoporphyrin IX (PpIX lipid) was inserted via centrifugation, creating a novel photosensitizer named porphyrus envelope [1]. We herein report how porphyrus envelope allows rapid drug delivery via membrane fusion and exhibits high therapeutic efficacy. Methods: In vitro drug release mechanism of porphyrus envelope was analysed using transmission electron microscope (TEM). Next, localization of porphyrus envelope-PpIX lipid was analysed